Malaria in pregnancy is a major public health problem in Tanzania and many other countries in sub-Saharan Africa. Malaria is associated with tremendous morbidity in the mother including severe anemia, and in the fetus in the form of low birth weight and fetal loss. Vitamin A and zinc deficiencies are specific factors which can modulate the clinical course of malaria and exacerbate associated complications. The published literature suggests that these two micronutrients favor a reduction in risk of placental malaria and related clinical outcomes including malaria and anemia among women, and low birth weight. We propose to study the efficacy of zinc and/or vitamin A supplementation in reducing the risk of placental malaria and other maternal/fetal outcomes. We will recruit 9,000 women of reproductive age and follow them up on monthly basis for pregnancy status, and identify and randomize our target sample of 2500 pregnant women. Subjects eligible for randomization will be HIV-negative women who are at or before 8 weeks of gestation. Women will be enrolled using a factorial design and assigned to receive zinc alone, vitamin A alone, both zinc and vitamin A, or placebo. All women will receive daily folate and iron supplements as per standard prenatal care. Women, and after delivery babies, will be followed up until 6 weeks after delivery. Compliance with supplement use will be assessed by direct questioning of women and pill count at monthly clinic visits. Biochemical assessment of compliance will also be assessed measuring the plasma concentration of vitamin A and zinc in a random subsample of 400 women at randomization, at 30 weeks of gestation, and at delivery. The primary endpoint is placental malaria, and secondary endpoints include maternal malaria, maternal anemia, and low birth weight. We propose to examine key aspects of the humoral and cell-mediated immune response to malaria in a sub-study. The program will be carried out by Harvard School of Public Health in collaboration with Muhimbili University of Health and Allied Sciences in Dar es Salaam, Tanzania. PUBLIC HEALTH RELEVANCE: Vitamin A and zinc supplementation during pregnancy have the potential to boost the immune response to prevent placental malaria and/or avoid clinical complications associated with it such as maternal anemia and low birth weight in the infants. However, the safety and efficacy of such supplements in pregnant women has not been examined. The proposed study will address this research question and will provide evidence that may lead to an optimization of international guidelines on vitamin A and zinc supplementation in pregnant women that will be important for more than 25 million women becoming pregnant in malaria-endemic regions in Africa every year.